The present invention relates to a method for resolving optical isomers.
Optical antipodes obtained by optical resolution are widely used as various chemical products, for example, as agricultural chemicals, drugs, food additives and their intermediates.
Optical antipodes include optically active halogen-containing compounds, amino acids, amino acid derivatives, carboxylic acids, carboxylic acid derivatives, amine-containing compounds, alcohol compounds, hydroxycarboxylic acids, hydroxycarboxylic acid derivatives, etc.
Long-established methods for obtaining optical antipodes from optical isomers by optical resolution include preferential precipitation methods, diastereomeric salt precipitation methods, etc. (Kikan Kagaku Sosetsu, Separation of Optical Isomers (in Japanese), No. 6, 1989, Gakkai Shuppan Center).
In addition to the above methods, various optical resolution methods are proposed. For example, optical resolution methods by liquid chromatography (adsorption separation), optical resolution methods using any separation membrane for optical resolution with an optically active source immobilized in a membrane, etc. are available.
In the adsorption separation of optical isomers, adsorption separation using an adsorbent with an optically active source immobilized is widely known. For example, known adsorbents for adsorption separation of optical isomers include polysaccharide derivatives (esters of cellulose, amylose, etc., carbamates, etc.), carried or not carried by silica gel, cyclodextrin derivatives, carried or not carried by silica gel, etc., polyacrylate derivatives carried or not carried by silica gel, etc. Adsorption separation of optical isomers by use of polysaccharide derivatives is reported by Yajima and Okamoto (Bull. Chem. Soc. Jpn., 68, 3289-3307 (1995). Furthermore, a method for resolving optical isomers using,an adsorbent and a mobile phase containing an optical antipode with a structure similar to that of the optical isomers to be resolved is disclosed in FR2593409.
For distillation separation of optical isomers, a resolution method by extractive distillation is disclosed in FR2176621A. Furthermore, HU212256B discloses a method for resolving amphetamine-enantioisomers by fractional distillation.
Moreover, compounds similar or identical to cyclodextrin derivatives used as discriminating agents in the present invention are disclosed in EP407412B and US4948395 as compounds of a stationary phase for optical isomer resolution.
One compound (optical antipode) can be removed from of optical isomers by various methods as described above. However, since the needs for resolving optical isomers are not perfectly satisfied by these known methods, a new resolution method is being demanded. Since preferential precipitation methods and diastereomeric salt precipitation methods need a solid-liquid separation step, they must be carried out as a batch process causing such problems as low productivity and complicated operation.
In the conventional adsorption separation methods for optical isomers, as can be seen typically from adsorbents having a polysaccharide derivative, etc. carried by silica gel, the adsorbents have generally low mechanical strength, and it is difficult to use them in an industrial separation process. Furthermore, these adsorbents are very expensive since they are produced in long processes, and moreover since they have a polysaccharide derivative simply carried, the polysaccharide derivative is disadvantageously eventually dissolved out. In the case of the resolution method using a mobile phase containing an optical antipode disclosed in FR2593409, etc., any device for recycling the mobile phase desirable in industrial separation and the requirements necessary for efficient industrial production are not referred to.
As a conventional distillation separation method for optical isomers, a resolution method by extractive distribution separation is disclosed in FR2176621A. The invention presents an idea concerning the resolution of optical isomers by use of an extracting agent, but it leaves many problems to be solved such as the recycling of the extracting agent and the selection of an optimum extracting agent. HU212256B discloses a resolution method for amphetamine.enantioisomers by fractional distillation. In the invention, a specific resolving agent and amphetamine isomers to be resolved are homogenized, to obtain a specific optical antipode by fractional distillation, but since the homogenization step (for example, a diastereomeric clathrate compound is preferentially precipitated) is necessary, no continuous highly productive process can be performed.
Moreover, since there is no one adsorption separating agent which can separate all of many optical isomers, the development of various new adsorption separating agents and separation systems is desired.
A new optical resolution method which can solve these various problems is demanded and is an object of this invention.
We have found that optical isomers can be efficiently resolved by a method for in which a discriminating liquid, comprising a discriminating agent capable of discriminating optical isomers and a diluent, is brought into contact with a mixture containing the optical isomers in counter current flow, and to resolve the optical isomers by adsorption separation, distillation separation, absorption separation or membrane separation. The discriminating liquid is recycled at an optical isomer content of 5 wt % or less. One or more of the following conditions is present in the resolving step:
(a) The dielectric constant of the diluent is 30 or less and the viscosity of the discriminating liquid is 0.2 Paxc2x7s or less at the temperature of the resolving operation.
(b) The discriminating agent has the property of splitting the 1H or 13C-NMR spectrum peak of the optical isomers and the diluent has a dielectric constant equal to or lower than the dielectric constant of the measuring solvent at the time of measuring the 1H or 13C-NMR spectrum.
(c) The boiling point of at least one compound of the discriminating agent, at the pressure of the resolving operation is higher than the boiling point of at least one compound of the diluent at the pressure of the resolving operation.
(d) The boiling point of at least one compound of the diluent at the pressure of the resolving operation is higher by 10xc2x0 C. or more than the boiling point of the optical isomers to be resolved, at the pressure of the resolving operation
(e) The concentration of the discriminating agent in the discriminating liquid is 10 wt % or more.